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Intravital measurements of solid stresses in tumours reveal length-scale and microenvironmentally dependent force transmission

Nature Biomedical Engineering volume 7, pages 1473–1492 (2023)Cite this article

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Abstract

In cancer, solid stresses impede the delivery of therapeutics to tumours and the trafficking and tumour infiltration of immune cells. Understanding such consequences and the origin of solid stresses requires their probing in vivo at the cellular scale. Here we report a method for performing volumetric and longitudinal measurements of solid stresses in vivo, and findings from its applicability to tumours. We used multimodal intravital microscopy of fluorescently labelled polyacrylamide beads injected in breast tumours in mice as well as mathematical modelling to compare solid stresses at the single-cell and tissue scales, in primary and metastatic tumours, in vitro and in mice, and in live mice and post-mortem tissue. We found that solid-stress transmission is scale dependent, with tumour cells experiencing lower stresses than their embedding tissue, and that tumour cells in lung metastases experience substantially higher solid stresses than those in the primary tumours. The dependence of solid stresses on length scale and the microenvironment may inform the development of therapeutics that sensitize cancer cells to such mechanical forces.

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Fig. 1: The workflow of in vivo solid stress measurement in primary and metastatic tumours.
Fig. 2: Validation and sensitivity analysis of solid stress measurement at the cellular and tissue scales in vivo.
Fig. 3: Solid stress transmission is scale dependent: in vivo solid stresses experienced by cancer cells at the cellular scale is significantly lower than solid stresses experienced at the tissue scale.
Fig. 4: Longitudinal and spatial measurements of solid stresses in vivo at the cellular scale.
Fig. 5: Measurement of solid stress in breast cancer lung metastases in a functioning lung.
Fig. 6: Measurement of solid stresses that individual cells experience in blood vessels using cellular-scale beads as surrogates for single cells.
Fig. 7: In vitro models of tumours faithfully model the solid stresses levels in vivo at the cellular scale.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, yet they are available for research purposes from the corresponding authors on reasonable request. Source data are provided with this paper.

Code availability

MATLAB codes are available at https://github.com/suezhangBU/solid_stress.

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Acknowledgements

We thank the Neurophotonics Center at Boston University for their generous support and access to their facility. Research reported in this publication was supported by the Boston University Micro and Nano Imaging Facility and the Office of the Director, National Institutes of Health of the National Institutes of Health under award number S10OD024993. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health. H.T.N. discloses support for the research described in this study from the National Institutes of Health (DP2HL168562 and R21EB031332, to H.T.N.), Beckman Young Investigator Award (to H.T.N.), Boston University Center for Multiscale and Translational Mechanobiology (to S. Zhang, K.R. and H.T.N.), and the American Cancer Society Institutional Fund at Boston University (to H.T.N.). M.W.G. discloses support from the National Institutes of Health (T32EB006359 to S. Zhang and M.W.G.).

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Authors and Affiliations

  1. Department of Biomedical Engineering, Boston University, Boston, MA, USA

    Sue Zhang, Gabrielle Grifno, Rachel Passaro, Kathryn Regan, Siyi Zheng, Muhamed Hadzipasic, Rohin Banerji, Logan O’Connor, Vinson Chu, Sung Yeon Kim, Jiarui Yang, Linzheng Shi, Kavon Karrobi, Darren Roblyer, Mark W. Grinstaff & Hadi T. Nia

  2. Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA

    Muhamed Hadzipasic

  3. Department of Chemistry, Boston University, Boston, MA, USA

    Mark W. Grinstaff

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Contributions

S. Zhang and H.T.N. conceived the project and wrote the manuscript; S. Zhang conducted most of the experiments, performed data analysis and generated the experimental mice; R.P. assisted with collecting and analysing spheroid data; K.R. generated the image segmentation and ellipsoid-fitting codes; M.H. collected Young’s modulus data of cells, spheroids and tumours with AFM; G.G. generated lung metastasis models and performed lung extraction and imaging; S. Zheng collected mechanical data on PA hydrogels; L.O. assisted with the design and fabrication of the intravital window and imaging stage; V.C. assisted with PA bead fabrication; S.Y.K. assisted with generating code for defining bead deformations; J.Y. assisted with OCT imaging; R.B. provided materials for lung imaging; L.S. performed liver and brain experiments, K.K., D.R. and M.W.G. contributed to discussions on crucial aspects of the project; H.T.N. supervised the project and provided guidance on experimental design, data interpretation and writing of the manuscript.

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Correspondence to Hadi T. Nia.

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Extended data

Extended Data Fig. 1 Window implantation after tumour growth causes artificial compression.

a, Methodology and timeline for tumour induction. The outlined image was taken using a fluorescent stereomicroscope. b, After showing that window implantation after tumour formation applies artificial compression, which relaxes over 6 days, we switched to window implantation before the tumour induction. Window implantation before tumour induction does not alter the solid-stress level (Fig. 2h). The XZ and XY views of the bead (E = 1.3 ± 0.13 kPa) in the tumour at days 0, 3, and 6, captured with OCT. c, Aspect ratios of polyacrylamide beads over time (mean ± STD, n = 3–6 beads).

Extended Data Fig. 2 Longitudinal in vivo imaging of MCa-M3C-H2B-dendra2 tumours at the cellular and tissue scale.

a, Cellular-scale beads (0.77 ± 0.16 kPa) were imaged up to 7 days via two-photon microscopy (cancer cells (green), polyacrylamide beads (magenta)). b, Tissue-scale beads (E = 1.3 ± 0.13 kPa) were tracked up to 14 days via optical coherence microscopy (polyacrylamide bead (outlined in yellow)). The experiments were performed independently in 3 (cellular scale) and 2 (tissue scale) mice, with similar results.

Supplementary information

Source data

Source data

Source data for the tumour-growth plot shown in Supplementary Fig. 7.

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Zhang, S., Grifno, G., Passaro, R. et al. Intravital measurements of solid stresses in tumours reveal length-scale and microenvironmentally dependent force transmission. Nat. Biomed. Eng 7, 1473–1492 (2023). https://doi.org/10.1038/s41551-023-01080-8

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  • DOI: https://doi.org/10.1038/s41551-023-01080-8

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